- The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR
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Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits. Recently, several metabolites have been identified that modulate ageing; however, the molecular mechanisms underlying this are largely undefined. Here we show that α-ketoglutarate (α-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit β 2 is identified as a novel binding protein of α-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS). The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan. We show that α-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by α-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by α-KG requires ATP synthase subunit β and is dependent on target of rapamycin (TOR) downstream. Endogenous α-KG levels are increased on starvation and α-KG does not extend the lifespan of dietary-restricted animals, indicating that α-KG is a key metabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.
- Chin, Randall M.,Fu, Xudong,Pai, Melody Y.,Vergnes, Laurent,Hwang, Heejun,Deng, Gang,Diep, Simon,Lomenick, Brett,Meli, Vijaykumar S.,Monsalve, Gabriela C.,Hu, Eileen,Whelan, Stephen A.,Wang, Jennifer X.,Jung, Gwanghyun,Solis, Gregory M.,Fazlollahi, Farbod,Kaweeteerawat, Chitrada,Quach, Austin,Nili, Mahta,Krall, Abby S.,Godwin, Hilary A.,Chang, Helena R.,Faull, Kym F.,Guo, Feng,Jiang, Meisheng,Trauger, Sunia A.,Saghatelian, Alan,Braas, Daniel,Christofk, Heather R.,Clarke, Catherine F.,Teitell, Michael A.,Petrascheck, Michael,Reue, Karen,Jung, Michael E.,Frand, Alison R.,Huang, Jing
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- Synthesis of the 1-monoester of 2-ketoalkanedioic acids, for example, octyl α-ketoglutarate
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Oxidative cleavage of cycloalkene-1-carboxylates, made from the corresponding carboxylic acids, and subsequent oxidation of the resulting ketoaldehyde afforded the important 1-monoesters of 2-ketoalkanedioic acids. Thus ozonolysis of octyl cyclobutene-1-carboxylate followed by sodium chlorite oxidation afforded the 1-monooctyl 2-ketoglutarate. This is a cell-permeable prodrug form of α-ketoglutarate, an important intermediate in the tricarboxylic acid (TCA, Krebs) cycle and a promising therapeutic agent in its own right.
- Jung, Michael E.,Deng, Gang
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p. 11002 - 11005
(2013/02/22)
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- ALPHA-KETOGLUTARATES AND THEIR USE AS THERAPEUTIC AGENTS
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The present invention relates generally to the field of pharmaceuticals and medicine. More particularly, the present invention relates to certain compounds (e.g., α-ketoglutarate compounds; compounds that activate HIFα hydroxylase; compounds that increases the level of α ketoglutarate, etc.) and their use in medicine, for example, in the treatment of cancer (e.g., cancer in which the activity of one of the enzymes in the tricarboxylic acid (TCA) cycle is down regulated), in the treatment of angiogenesis (e.g., hypoxia-induced angiogenesis). One preferred class of compounds are α-ketoglutarate compounds having a hydrophobic moiety that is, or is part of, an ester group formed from one of the acid groups of α ketogluartic acid; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, N oxides, chemically protected forms, and prodrugs thereof.
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Page/Page column 61
(2008/06/13)
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